Peg conjugates of exenatide

a technology of exenatide and conjugates, which is applied in the field of slow release conjugates of exenatide, can solve the problems of short circulating half-life and ineffectiveness of glp-1 as a therapeutic agen

Inactive Publication Date: 2014-09-11
PROLYNX LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

GLP-1 is ineffective as a therapeutic agent as it has a very short circulating half-life (less than 2 minutes) due to rapid degradation by dipeptidyl peptidase-4.
(2004) 279:38118-38124), but these suffer from residual activity of the conjugates as well as relatively fast drug release rates (t1 / 2˜12 h) that are not optimal to support extended-duration delivery of exenatide.

Method used

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  • Peg conjugates of exenatide
  • Peg conjugates of exenatide
  • Peg conjugates of exenatide

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Azido-Linker-OSu

[0065]

[0066](1) 6-azido-1-hexanol: a mixture of 6-chloro-1-hexanol (25 g, 183 mmol) and sodium azide (32.5 g, 500 mmol) in 200 mL of water was heated at reflux for 20 h, then cooled to ambient temperature and extracted 3× with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated to yield the product as a pale yellow oil (28.3 g).

[0067](2) 6-azidohexanal: Solid trichloroisocyanuric acid (4.3 g) was added in small portions to a vigorously stirred mixture of 6-azido-1-hexanol (7.15 g), TEMPO (50 mg), and sodium bicarbonate (5.0 g) in dichloromethane (100 mL) and water (10 mL). The mixture was stirred for an additional 30 minutes after addition, then filtered through a pad of Celite. The organic phase was separated and washed successively with sat. aq. NaHCO3 and brine, then dried over MgSO4, filtered, and concentrated to provide the product (5.8 g), which was used without further purification.

[0068](3) ...

example 2

Preparation of Azido-Linker-Exenatides

[0081]

[0082]Fmoc-TentaGel® Rink amide resin (0.17 meq / g) was used to synthesize protected exenatide using standard Fmoc / tBu chemistry. The resin was allowed to swell in dichloromethane and then washed with N,N-dimethylformamide (DMF). Fmoc groups were removed using piperidine. Coupling steps were performed using O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) and N-methylmorpholine in DMF. After removal of the final Fmoc group and washing, the resin was treated with 3 molar equivalents (based on resin substitution) of the azido-linker-OSu (Example 1) and 3 molar equivalents of N,N-diisopropyl-ethylamine in DMF. Reaction progress was followed by ninhydrin test. After 2 h, the resin was washed with methanol and ether, then dried. Cleavage and deprotection of the product used a mixture of trifluoroacetic acid / triisopropylsilane / water for 4 h. The crude product was then precipitated with ether, and purified by HPLC using a ...

example 3

Preparation of GL4-400-DBCO

[0089]

[0090]A solution of a 4-branched mPEG-amine (GL4-400-PA, NOF Corporation) of mw=40 kDa (1.0 g, 25 μmol) in 10 mL of THF was reacted with DBCO-NHS (24 mg, 50 μmol) and triethylamine (7 μL) for 24 h at ambient temperature. Precipitation into 50 mL of MTBE provided 0.9 g of the 4-branched GL4-400-PA-DBCO.

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Abstract

Slow release forms of exenatide wherein exenatide is releasably linked to polyethylene glycol carriers are disclosed.

Description

RELATED APPLICATION[0001]This application claims benefit of U.S. application Ser. No. 61 / 548,579 filed 18 Oct. 2011 which is incorporated herein by reference in its entirety.TECHNICAL FIELD[0002]The invention relates to slow release conjugates of exenatide.BACKGROUND ART[0003]Exenatide (exendin-4) is a 39-amino acid peptide isolated from the saliva of the Gila monster, Heloderma suspectum, by Eng in 1992. It is an insulin secretagogue with glucoregulatory effects similar to the human peptide glucagon-like peptide-1 (GLP-1), and has been approved for the treatment of Type II diabetes.[0004]The incretin hormones GLP-1 and glucose-dependent insulinotropic peptide (GIP) are produced by the L and K endocrine cells of the intestine following ingestion of food. GLP-1 and GIP stimulate insulin secretion from the beta cells of the islets of Langerhans in the pancreas. Only GLP-1 causes insulin secretion in the diabetic state. GLP-1 is ineffective as a therapeutic agent as it has a very short...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/48
CPCA61K47/48215A61K38/00A61K47/60A61P3/10
Inventor SANTI, DANIEL V.SCHNEIDER, ERIC L.ASHLEY, GARY W.
Owner PROLYNX LLC
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